Reproducibility and optimization of in vivo human diffusion-weighted MRS of the corpus callosum at 3T and 7T

Diffusion-weighted MRS (DWS) of brain metabolites enables the study of cell-specific alterations in tissue microstructure by probing the diffusion of intracellular metabolites. In particular, the diffusion properties of neuronal N-acetylaspartate (NAA), typically co-measured with N-acetylaspartyl glutamate (NAAG) (NAA+NAAG=tNAA), have been shown to be sensitive to intraneuronal/axonal damage in pathologies such as stroke and multiple sclerosis. Lacking, so far, are empirical assessments of the reproducibility of DWS measures across time and subjects, as well as a systematic investigation of the optimal acquisition parameters for DWS experiments, both of which are sorely needed for clinical applications of the method. In this study, we acquired comprehensive single-volume DWS datasets of the human corpus callosum at 3T and 7T. We investigated the inter- and intra-subject variability of empirical and modeled diffusion properties of tNAA [D_avg(tNAA) and D_model(tNAA), respectively]. Subsequently, we used a jackknife-like resampling approach to explore the variance of these properties in partial data subsets reflecting different total scan durations. The coefficients of variation (C_V) and repeatability coefficients (C_R) for D_avg(tNAA) and D_model(tNAA) were calculated for both 3T and 7T, with overall lower variability in the 7T results. Although this work is limited to the estimation of the diffusion properties in the corpus callosum, we show that a careful choice of diffusion-weighting conditions at both field strengths allows the accurate measurement of tNAA diffusion properties in clinically relevant experimental time. Based on the resampling results, we suggest optimized acquisition schemes of 13-min duration at 3T and 10-min duration at 7T, whilst retaining low variability (C_V≈8%) for the tNAA diffusion measures. Power calculations for the estimation of D_model(tNAA) and D_avg(tNAA) based on the suggested schemes show that less than 21 subjects per group are sufficient for the detection of a 10% effect between two groups in case-control studies.